Current global surveillance indicates that multidrug resistant (MDR) bacteria are emerging at an alarming rate. There is also a significant concern regarding the possibility that genetic engineering and synthetic biology may result in the creation of highly virulent microorganisms. In view of the potential threat of rapidly occurring and spreading virulent microorganisms and antimicrobial resistance, alternative clinical treatments against bacterial infection must be sought and developed.
Bacteriophages (“phages”) are diverse viruses that replicate within and can kill specific bacterial hosts. The possibility of harnessing lytic phages as an antibacterial was investigated following their initial isolation early in the 20th century, and they have been used clinically as antibacterial agents in some countries with some success. Notwithstanding, phage therapy was largely abandoned in the U.S. subsequent to the discovery of penicillin, and only recently has interest in phage therapeutics been renewed. For example, engineered phages have been used as therapeutic delivery systems e.g., natural phages covalently attached to antibiotics, pathogen-targeted peptide displays on the surface of a phage, and bacteria specific CRISPR (clustered regularly interspaced short palindromic repeats)-Cas systems for silencing antibiotic resistance genes. Components of phage have also been used as antibacterial agents (e.g., cloning phage genes) such as lysozymes, endolysin, and phage tail-associated muralytic lytic enzymes (TAME).
Phages are typically highly specific for a particular bacterial host and thus can be used clinically to target a bacterial pathogen. Unfortunately, however, due to phage-bacterial host specificity, so called broad spectrum phage products against numerous bacterial strains, even of the same pathogenic bacterial species, are difficult to develop; a previously effective phage therapy can quickly become ineffective during clinical treatment as the target bacterial host is eliminated and is naturally replaced by one or more emergent phage-resistant bacterial strains. In fact, pre-existing phage-resistance and/or emergent phage-resistance in a bacterial population is to be expected whenever a phage and a bacterial population interact, and unless steps are taken to also target these resistant mutants in the bacterial population, these mutants will simply be selected-for and will outgrow once the phage eliminate the susceptible fraction of the population. Thus, currently, the clinical usefulness of phage therapy remains limited at best, and there remains a need for improved methods and formulations for using phage as antibacterial agents. Specifically, there remains a need for methods which permit the rapid and reliable compounding of therapeutic compositions comprising one or more phages, wherein said composition is not only custom designed (“personalized”) to treat an infection caused by a particular bacterial strain in a subject in need thereof, but is also able to overcome the expected phage-resistant bacterial mutant strains that will outgrow during treatment, so as to allow therapeutic efficacy.